Much of the increased safety of heart surgery has come from improved surgical techniques which can be used when the heart is still and quiet. A quiet heart is usually produced by cooling and depriving it of its blood supply. In addition, a cardioplegic solution is frequently injected into the vessels of the heart to produce cardiac standstill. Although these techniques have allowed enormous strides in cardiac surgery, there is still a price to be paid for this period of ischemia. The result is a period of depressed function (low cardiac output) following the operation which may or may not be reversible. Moreover, even if reversed for the short term, there is evidence that scarring can occur and later failure can result. Failure of recovery from ischemia due to myocardial infarctions or open heart surgery accounts for about 500,000 deaths per year in the United States.
As in other tissues, myocardial cell function and integrity require adenosine triphosphate (ATP) as the primary energy source. It is well known that both myocardial ATP levels and function are severly depressed by ischemia, and the recovery of cardiac energy metabolism after a period of ischemia has been widely investigated. Several important points have been established: (1) ATP levels do not rebound quickly with blood reperfusion, (2) the failure of this recovery is not due to impaired mitochondrial function because creatine phosphate levels rebound quickly to pre-ischemic values with reperfusion and cellular oxygen consumption is normal and (3) the factor that appears to limit most ATP regeneration is the enzymatic degradation and cellular leakage of ATP precursors.
During ischemic insult of a tissue, with concomitant hypoxia, the cellular energy reservoir of ATP is hydrolyzed first to adenosine diphosphate (ADP), then to adenosine monophosphate (AMP), adenosine (Ad) and finally adenine (A). Following reperfusion of blood, the energetic recovery via the synthesis of high energy ATP bonds in the cell is limited because of loss of these ATP precursors. Adenosine and adenine leak out of the cells, and adenine is further catabolized to end products and cannot reenter the cycle. Endogenous synthesis of ATP precursors through the purine biosynthetic pathway, the major normal route of synthesis, proceeds slowly, is metabolically demanding, and thus limits ATP recovery.
After a period of myocardial ischemia under the conditions of clinical open heart surgery, ATP levels require about ten days to fully recover. Myocardial function has been determined to require a similar period for full return. The most sensitive aspect of myocardial function was found to be the relaxation rather than the contraction phase of the heartbeat. It is the relaxation phase, or diastole, that requies almost ten days to return to normal. When relaxation ia incomplete, the heart does not fill satisfactorily and, therefore, less blood is ejected with each beat.
The theory that a reduction in the ATP recovery time could lead to improved cardiac function has lead to research aimed both at preventing the initial loss of ATP precursors from the cell and at methods for the resupply of the precursors employed in ATP biosynthesis.
Many investigators have attempted to show that precursor infusion will augment ATP recovery. Adenosine, adenine, inosine, 5-amino-4-imidazolcarboxamide riboside and ribose are some of the ATP precursors that have been marginally useful in increasing ATP regeneration after ischemia. Most studies were of short duration and only partial ATP recovery was found. Furthermore, percursors which are relatively distant in terms of the enzymatic steps required to reform ATP may be less efficient in inducing ATP recovery, while structurally more-closely related ATP precursors such as adenosine exhibit undesirable side-effects such as renal vasoconstriction or slowed atrioventricular conduction.
Therefore, the need exists for a method to improve the recovery of myocardial function after partial or total occlusion. A need also exists for a general method for the treatment of ischemic tissue to quickly restore normal ATP levels, both to improve tissue survival and to hasten general bodily recovery.